Reviews in Medical Virology

REVIEW

Rev. Med. Virol. 2014; 24: 55–70. Published online 14 November 2013 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/rmv.1773

Fc gamma receptors in respiratory syncytial virus infections: implications for innate immunity Jop Jans1,2, Marloes Vissers1,2, Jacco G.M. Heldens1,3, Marien I. de Jonge1,2, Ofer Levy4,5 and Gerben Ferwerda1,2* 1

Department of Pediatrics, Laboratory of Pediatric Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands 2 Nijmegen Institute for Infection, Inflammation and Immunity, Radboud University Medical Centre, Nijmegen, The Netherlands 3 Nobilon International BV, Boxmeer, The Netherlands 4 Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 5 Harvard Medical School, Boston, MA, USA

S U M M A RY RSV infections are a major burden in infants less than 3 months of age. Newborns and infants express a distinct immune system that is largely dependent on innate immunity and passive immunity from maternal antibodies. Antibodies can regulate immune responses against viruses through interaction with Fc gamma receptors leading to enhancement or neutralization of viral infections. The mechanisms underlying the immunomodulatory effect of Fc gamma receptors on viral infections have yet to be elucidated in infants. Herein, we will discuss current knowledge of the effects of antibodies and Fc gamma receptors on infant innate immunity to RSV. A better understanding of the pathogenesis of RSV infections in young infants may provide insight into novel therapeutic strategies such as vaccination. Copyright © 2013 John Wiley & Sons, Ltd. Received: 12 August 2013; Revised: 11 October 2013; Accepted: 14 October 2013

INTRODUCTION RSV can cause bronchiolitis that is a major burden in infants because almost all children will have had an RSV infection by the age of 2 years [1,2]. The severity of RSV infection ranges from mild upper respiratory symptoms to severe lower respiratory tract infection resulting in mechanical ventilation and admission to an intensive care unit. Strikingly, severe infections occur predominantly in infants below 6 months of age and usually involve

*Corresponding author: G. Ferwerda, MD PhD. Department of Pediatrics, Laboratory of Pediatric Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands. E-mail: [email protected] Abbreviations used ADCC, antibody-dependent cellular cytotoxicity; ADE, antibodydependent enhancement; BCR, B cell receptor; C3aR, complement 3a receptor; ECP, eosinophil cationic protein; FcγR, Fc gamma receptor; fMLP, formyl-methionyl-leucyl-phenylalanine; matAbs, maternal antibodies; NS protein, non-structural protein; PMA, phorbol 12,13-dibutyrate; sG, soluble G protein; TLR, Toll-like receptor.

Copyright © 2013 John Wiley & Sons, Ltd.

primary infections. Risk factors such as prematurity, lung disease, and congenital heart disease only account for ~50% of the severe cases [1]. It is currently unknown which other factors may account for the remaining 50% of patients with severe RSV infections.

Control of RSV infection in early life Infants below 6 months of age are largely dependent on innate immunity and the presence of matAbs during infectious diseases. As severe RSV cases involve primary infections, innate immunity and matAbs are likely to have an important role. This raises the question why severe RSV infections are highly prevalent in a population having matAbs. This lack of protection might be due to the matAb properties and/or inefficient interaction between these matAbs and the innate immune system. Innate immunity comprises particular cells and mechanisms that are the first line of defense against infections after the physical barrier has been

56 breached. It is composed of innate immune cells and soluble components such as the complement system, antimicrobial proteins, and peptides. Cells such as monocytes, macrophages, dendritic cells, NK cells, and granulocytes contain specific pathogenrecognition molecules, for example, TLRs, which induce the production of cytokines and activate the adaptive immune response. The innate immune response is supported by a soluble biochemical host defense cascade known as the complement system. Upon activation, this system complements the ability of Abs and phagocytic cells to clear pathogens. Because of an immature adaptive immune system and limited antigen (Ag) encounter in utero, neonates and infants below 6 months of age rely particularly on their still maturing innate immune system to defend themselves against infectious diseases [3]. The importance of innate immune receptors at this age is illustrated by the fact that deficiencies in TLR signaling increase susceptibility to infections with Streptococcus spp., Listeria monocytogenes, RSV, and Toxoplasma gondii in the first years of life [4]. MatAbs are produced by the mother after infection or vaccination. The induction of high-affinity Ag-specific Abs is called affinity maturation and leads to high avidity, neutralizing Abs. During pregnancy, matAbs are transferred across the placenta to the fetus and remain in the serum of infants during the first months of life. Immunoglobulins, mainly IgG1, IgG3, and IgG4, cross the placenta actively and are the most important matAbs [5]. IgM is a molecule too large to be transported across the placenta, and IgA is transferred to the neonate in small amounts through breast milk [6]. The importance of matAbs is illustrated in newborns with a genetic inability to produce Abs such as agammaglobulinemia. These patients are usually protected against invasive bacterial infections up to 6 months when matAbs are still present [7]. FcγRs are essential for the recognition of IgG and internalization of immune complexes to induce an immune response. FcγRs can be divided into either activating or inhibitory receptors, and all innate immune cells contain their own specific set of FcγRs. B cells only express the inhibitory FcγRIIB (Table 1). The balance between activating and inhibitory FcγRs together with the avidity of this binding determines the threshold to immune activation [8]. Interaction between FcγRs and pathogen-recognition receptors and the complement system as components of the innate immune system has been Copyright © 2013 John Wiley & Sons, Ltd.

J. Jans et al. described, and the role of IgG in this cross-talk is currently being elucidated [9–11] (Figure 1.) In this review, we will discuss the presence and the properties of RSV-specific Abs in infants and elaborate on the interaction between Abs, FcγRs, and the innate immune system, both in general and in RSV infections. RSV-SPECIFIC ANTIBODIES IN INFANTS RSV-specific matAbs are present during the first 6 months of life and have an estimated half-life of 1.5 months [12–15]. IgG1 (66%) and IgG3 (5.3%) are the predominant subtypes present in infants [16–20]. These titers are highest among infants 24 months, possibly indicating matAbs and “self-made antibodies”, respectively. Furthermore, RSV-specific IgG2 and IgG4 are not detected in the sera [20]. The clinical relevance of RSV-specific IgG is unknown at this moment, and conflicting evidence is present regarding the effects of matAbs. Several studies observed that matAbs do not have a clinically beneficial effect and high anti-RSV Ab levels are associated with an increased risk of recurrent wheezing [21–23]. Other studies indicate that high titers of maternal IgG are associated with protection against RSV infection [23–27]. These studies calculated the amount of IgG by investigating the neutralizing effect of the sera via plaque reduction or the reduction of the RSV-induced cytopathic effect in in vitro cell culture systems. The amount and effect of non-neutralizing Abs are not measured by these methods. An EIA without preselecting neutralizing Abs might more accurately represent the total amount of RSV-specific IgG. By using an EIA, a marginal increased risk of hospitalization has been associated with moderate levels of matAbs compared with low levels [28]. RSVinfected infants have comparable amounts but significantly lower avidity of RSV-specific IgG1 compared with non-RSV-infected infants. These data indicate that Ab properties, such as avidity, might play a role in RSV infections [20]. A more pronounced Ab response after RSV infection in individuals with low titers of matAbs has been observed, indicating that matAbs can inhibit the B cell response and the production of Abs [29,30]. Further, passive transfer of RSV-specific Abs in mice attenuates the titer and the neutralizing activity of Abs against F and G proteins expressed by vaccinia virus recombinants [31–33]. Rev. Med. Virol. 2014; 24: 55–70. DOI: 10.1002/rmv

Copyright © 2013 John Wiley & Sons, Ltd.

Phagocytosis Cytokine release ADEb Degranulationc

Effect

Phagocytosis Cytokine release ADEb ADCCe

Monocyte Macrophage Dendritic cell Neutrophil Basophil Eosinophil

FcγRIIA

The last column indicates inhibitory receptors. a Upon stimulation with IFN-γ. b Antibody-dependent enhancement of disease. c Mast cells. d In mice models. e Antibody-dependent cellular toxicity. f Interaction with FcγRIII. g B cells.

Complement activationd

Monocyte Macrophage Dendritic cell Neutrophil Eosinophil Mast cella

FcγRI

Expression

Type

Cytokine release ADCCe,f

NK cell

FcγRIIC

Phagocytosis Cytokine release Cross-talk TLR4 Complement activationd ADCCe

Monocyte Macrophage Dendritic cell NK cell Mast cell

FcγRIIIA

ADCCe

Phagocytosis Chemoattractants Cross-talk TLR4 Degranulationc

Neutrophil Eosinophila

FcγRIIIB

Reduced phagocytosis Reduced TLR signaling Reduced proliferation Apoptosisg

Monocyte Macrophage Dendritic cell Neutrophil Basophil Mast cell NK cell B cell

FcγRIIB

Table 1. Expression of different types of FcγR on innate cells and B cells and its proposed effect in the immune response against pathogens

Antibodies and FcγRs in RSV infection 57

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Figure 1. Interplay between FcγRs and other receptors on innate immune cells and B cells. FcγRs are expressed on APCs, NK cells, granulocytes, and B cells. Depending on the ITAM or ITIM motif, FcγRs can be divided in activating (blue) or inhibitory (red) receptors. Activating receptors are able to initiate cell activation and induce phagocytosis, ADCC, and the oxidative burst. Cross-talk with TLR-4 has been suggested for a proper immune response. The inhibitory FcγR, FcγRIIB, induces cell inhibition. Cross-talk between the complement system and activating FcγRs creates a positive feedback loop. Activating FcγRs (FcγRI and FcγRIII) promote the complement system to generate C5a. C5a binds C5aR, which is co-expressed on the cell. This binding induces increased expression levels of activating FcγRs and decreased levels of inhibitory FcγRs. B cells only express the inhibitory FcγR, FcγRIIB. Engagement of FcγRIIB to BCR leads to inhibition of cellular proliferation and induces apoptosis. (BCR, B cell receptor; C5aR, complement 5a receptor; ERK, extracellular-signal-regulated kinases; FcγR, Fc gamma receptor; IgG-IC, immune complex; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibition motif; LYN, member of src-related family of protein-tyrosine kinases; MyD88, myeloid differentiation primary response gene 88; RAS, member of small GTPase proteins; SHIP, SH2 domain containing inositol-5 phosphatase; Syk, spleen tyrosine kinase)

All together, these data suggest that matAbs alter the humoral response against RSV resulting in a non-protective immune response. Besides Ab properties, another important aspect to consider is the different epitopes that Abs can be directed to. RSV has several epitopes recognized by the immune system; the F protein, a surface glycoprotein, causes immune cell membranes to merge and mediates cell entry. The G protein is either membrane bound or secreted in a soluble form (sG) and has been implicated in immune evasion. The role of other viral proteins, such as the small hydrophobic protein and the NS proteins (NS1 and NS2), are less well defined and currently being investigated. The protective role of RSV-specific Abs is demonstrated by the introduction of palivizumab. Palivizumab is a monoclonal antibody (mAb) against the F protein of RSV and therefore reduces hospitalization and decreases the total number of wheezing days Copyright © 2013 John Wiley & Sons, Ltd.

in high-risk groups and preterm infants [34,35]. In mice, mAbs against the RSV G protein offer protection against respiratory disease. Both neutralizing and non-neutralizing anti-RSV G protein mAbs induce protection by inhibition of replication or reduction of pulmonary inflammation [36,37]. Given a halflife of 20 days, mAbs offer short-term protection and should be administered monthly. Therefore, the induction of a persistent protective immune response against RSV through vaccination has been a topic of interest for decades. The failure of a vaccine trial with formalin-inactivated RSV shows the complexity of inducing a proper immune response against RSV. Proper affinity maturation and the induction of neutralizing Abs are important for an adequate immune response against RSV [38,39]. Formalin-inactivated RSV induces nonneutralizing Abs and thereby causes an enhanced respiratory disease after concurrent RSV infection [39]. This process is mediated through insufficient Rev. Med. Virol. 2014; 24: 55–70. DOI: 10.1002/rmv

Copyright © 2013 John Wiley & Sons, Ltd.

Detectable in the minority of young infant Not detectable Monthly administration: - Reduced wheezing and hospitalizationd Low avidity: - Increased susceptibility to RSV infectionc High titer: - Increased wheezing and hospitalizationa - Reduced wheezing and hospitalizationb - Reduced Ab response Clinical relevance

IgG3 IgG2 mAb IgG1 (palivizumab) IgG1 Total IgG

FcγRI, FcγRIIA, and FcγRIIIA are involved in Abmediated phagocytosis of pathogens by monocytic cells such as monocytes, macrophages, and dendritic cells. Phagocytosis is important for the activation of Syk kinase and the induction of the immune response by release of inflammatory cytokines [42]. The downside of Ab-mediated phagocytosis is shown in the context of several viral infections and is called ADE. ADE has been observed in secondary dengue infections of both monocytes and dendritic cells in which Abs increase infectivity via FcγRI and FcγRIIA [43]. Furthermore, the ligation of dengue virus particles with Abs reduces the expression of TLR and shifts the formation of cytokines toward anti-inflammatory cytokines [44,45]. The same principle has been observed in the context of HIV infection and is dependent on FcγRs [46,47]. These data suggest a mechanism by which ADE in the context of viral infections increases infectivity and impairs the innate immune response [43,48]. A comprehensive review has been published concerning the different mechanisms of ADE in viral infections after secondary infections or vaccination [49]. Beside initiating phagocytosis, FcγRIII has been implicated in cross-talk with TLRs. The presence

Type

Fc gamma receptors and monocytes, macrophages, and dendritic cells

Table 2. Clinical relevance of IgG in RSV infections in young infants

THE EFFECT OF Fc GAMMA RECEPTORS ON INNATE IMMUNITY

IgG4

stimulation of TLR on B cells and is dependent on the formation of immune complexes. Inactivation of RSV with formalin induces reactive carbonyl groups that may alter immunogenicity and favor a Th2 response possibly resulting in pulmonary eosinophilia and deleterious immune responses [40]. An important regulatory role of CD8 T cells has been suggested because these cells inhibit RSV vaccine-enhanced disease and eosinophilia [41]. Consequently, a novel vaccine should induce a balanced CD4 and CD8 T cell response to minimize immunopathology. Overall, the clinical and immunological effects of RSV-specific Abs on RSV infection are still unclear. Studies have reported either protective or deleterious effect of matAbs (Table 2). Future research on the specific properties of matAbs is needed to interpret these contradictory data.

RSV-specific IgG can be divided into IgG1, IgG2, IgG3, IgG4, and mAb IgG1. Contradictory data are present regarding the protective effects of total maternal IgG. Low-avidity maternal IgG1 has been associated with an increased susceptibility to RSV infections. Palivizumab (mAb IgG1) has a protective effect against severe RSV infection in high-risk infants. IgG2-4 are either undetectable or only detected in the minority of young infants below the age of 6 months. a Amount of IgG measured by plaque reduction or reduction of RSV-induced cytopathic effect in in vitro cell culture system. b Amount of IgG measured by EIA. c Avidity measured by using an antibody eluting agent (sodium thiocyanate). d Administered to high-risk and preterm infants.

59 Not detectable

Antibodies and FcγRs in RSV infection

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J. Jans et al.

60 of immune complexes results in the association between TLR4 and FcγRIII. Furthermore, the activation of FcγR requires the presence and integrity of TLR4 because both FcγRIII-deficient mice and TLR4-deficient mice were unable to elicit an immune response upon stimulation of macrophages with IgG [11]. FcγRIIB is known as an inhibitory receptor resulting in immunosuppression and decreased phagocytosis by monocytic cells [50]. Pre-treatment of macrophages with IgG1 inhibits the TLR4 response induced by lipopolysaccharide, a process dependent on the activation of FcγRIIB [51]. In dendritic cells, blockage of FcγRIIB leads to dendritic cell maturation, up-regulation of the type I interferon genes, and increased amounts of chemokine c-c motif ligand 5, which underlines the inhibitory effects of FcγRIIB on the immune response [52,53].

The role of Fc gamma receptors expressed on monocytes, dendritic cells, and macrophages in RSV infections In animal studies, macrophages are essential for the restriction of RSV replication in the lungs. ADE after vaccination has been observed in RSV infections in vitro with both human and a mouse monocyte-like cell line and macrophages. Monoclonal Abs can have a neutralizing effect, a disease enhancing effect, or both [54]. The concentration of IgG and the simultaneous presence of different mAbs determine whether the Abs are neutralizing or disease enhancing [54,55]. The enhancing activity of RSV-specific Ab levels is confined to sera from infants aged 0–6 months and acts via FcγR [56]. This suggests that matAbs may contribute to ADE of RSV infection although ADE has not yet been investigated in the context of disease severity of RSV infections. Dendritic cells are the most important antigen-presenting cells and function as a bridge between innate and adaptive immunity. RSV can infect dendritic cells (DCs) but reduces T cell activation by impairment of the immunological synapse between DCs and T cells [57]. RSV-specific T cell activation and release of IFN-γ are enhanced when mouse DCs are exposed to RSV immune complexes. The use of FcγR-deficient mice showed that this process is dependent on activating FcγRs. The authors conclude that the presence of antibodies might induce a more efficient T cell response Copyright © 2013 John Wiley & Sons, Ltd.

through the phagocytosis of opsonized virus particles by DCs [58]. RSV has evolved different mechanisms to alter or counteract the antiviral effect of monocytic cells. RSV evades Ab neutralization by the production of sG, which acts as a decoy antigen. The use of FcγR-deficient mice shows that the production of sG decreases the antiviral effect of cells bearing FcγRs underlining the role of Abs in this process [59,60]. Other structural and NS proteins alter the antiviral immune response through direct interaction with recognition receptors [61–65]. All experiments in the context of human cells were performed in a serum-free environment. Therefore, the role of antibodies in the immune evasion mechanisms of RSV is unknown.

Fc gamma receptors and NK cells NK cells are activated by virus-infected cells directly through activation receptors or through immune complexes. FcγRIIIA is the most important FcγR present on NK cells [66]. In the context of Abs, CD56dim NK cells are of interest considering their abundant presence in peripheral blood and their expression of FcγRIIIA. IgG is able to enhance the production of cytokines by CD56dim NK cells upon encountering target cells [67]. Binding of immune complexes to FcγRIIIA induces ADCC through CD56dim NK cells by degranulation and perforin-dependent targeted cell lysis [68,69]. In the absence of a pathogen, IgG is able to inhibit NK cell activity [70]. ADCC has extensively been studied in the context of HIV infections in which the interaction of anti-HIV Abs with NK cells offers protection and even predicts viral load and clinical outcome [71,72]. ADCC against herpes simplex virus and HIV is decreased in neonates compared with adults possibly reflecting, in part, deficient interaction of matAbs and NK cells in the neonatal period [73–75]. FcγRIII is aided in its cytotoxic effect by FcγRIIC. Not all individuals express FcγRIIC on their NK cells. The FcγRIIC gene originates from the unequal crossover between IIA and IIB genes, which results in an FcγR that is homologous to FcγRIIB extracellularly and to FcγRIIA intracellularly [76]. When FcγRIIC is expressed on NK cells, it mediates IFN-γ production and aids FcγRIII in its cytotoxic effect [68,77]. Finally, the inhibitory FcγRIIB was detected in only a few individuals and was able to suppress NK cell function [76,78]. Rev. Med. Virol. 2014; 24: 55–70. DOI: 10.1002/rmv

Antibodies and FcγRs in RSV infection

The role of Fc gamma receptors expressed on NK cells in RSV infections In RSV-infected mice, NK cells accumulate in the lung upon RSV infection and cause acute lung injury through the production of IFN-γ [79,80]. RSV infection induces ADCC via NK cells as shown by the cytotoxic effect of NK cells on an RSV-infected human cell line. This process is already present in young infants, implying a role of matAbs [81,82]. Recent studies are unraveling the specific subsets of NK cells responsible for the RSV-induced ADCC. Lung tissues from fatal RSV infections showed a near absence of NK cells [83]. These low amounts of NK cells, however, might represent the end-stage values of NK cells considering the use of lung tissue samples after the patients died. In the acute phase of RSV infection, increased amounts of NK cells are found. CD56+/FcγRIIIA+ NK cells and IFN-γ production are increased in the acute phase of hospitalized patients with RSV infections compared with control patients without RSV infection [84]. The increased presence of FcγRIIIA+ NK cells, IFN-γ, and lung damage in severe RSV infections raises the possibility that IgG, as a ligand for FcγRIIIA, negatively influences the immune response in RSV infections. Fc GAMMA RECEPTORS AND GRANULOCYTES

61 polymorphonuclear leukocyte (PMN) from TLR4deficient mice are unable to elicit an immune response upon stimulation with IgG. However, the effect of immune complexes on PMN from FcγRIIIdeficient mice was not investigated [11]. The precise role of the inhibitory FcγRIIB in human neutrophils is as yet unknown. Resting human neutrophils express FCGR2B2 mRNA but express low levels of FcγRIIB on the cell surface. FcγRIIB might inhibit phagocytosis, superoxide production, and neutrophil adhesion [91].

The role of Fc gamma receptors expressed on neutrophils in RSV infections Neutrophils play an important role in the development of lung pathology in severe primary RSV infections in infants below 6 months [92]. Neither RSV alone nor RSV-specific Abs alone are able to activate neutrophils. The presence of RSV and RSVspecific Abs results in the formation of RSV immune complexes [93]. After phagocytosis of the immune complexes, profound activation of neutrophils and increased amounts of interleukin 8, oxygen radicals, and thromboxane B2 are observed. These products cause immune complex-mediated lung pathology and bronchoconstriction in RSV infections [93–95].

Mast cells Neutrophils Resting neutrophils express FcγRIIA in a lowavidity state, which is functionally inactive [85,86]. fMLP and PMA are two well-known neutrophil activators that regulate the functionality of FcγRIIA in an opposing manner. Whereas fMLP increases the binding of IgG-coated particles, PMA suppresses this process and thereby the functionality of FcγRIIA. These data indicate that the functionality of FcγRIIA is not merely dependent on the activation of neutrophils but that a stimulus-specific signal determines whether FcγRIIA on activated neutrophils becomes functionally active [87]. Future research investigating the effects of specific infectious agents, such as RSV, on the functionality of FcγRIIA is needed to translate these findings to understand its role in the pathophysiology of infectious diseases. The activation of FcγRIIIB leads to increased phagocytosis and the recruitment of neutrophils to inflammatory sites [88–90]. As stated before in the context of macrophages, stimulation of neutrophils with IgG results in the association between TLR4 and FcγRIII. Copyright © 2013 John Wiley & Sons, Ltd.

IgG Abs have been known to activate mast cells, long before the currently established correlation between IgE, mast cells, and allergic reactions [96]. Upon stimulation with IFN-γ, FcγRI expression on mast cells is upregulated, and IgG has an activating effect. The increased expression of FcγRI allows IgG, and particularly IgG1, to cause degranulation and prolonged survival of mast cells [97–99]. FcγRIIIA expression is present on mast cells and induces IgG-mediated degranulation [100,101]. Inhibition of Kit-induced mast cell proliferation upon activation of FcγRIIB has been observed, and bone marrow-derived mast cells do not respond to IgG unless they are FcγRIIB deficient [102]. These data suggest that IgG does bind to bone marrowderived mast cells but has an inhibitory effect through FcγRIIB that was confirmed by the increased sensitivity of mast cells from FcγRII-deficient mice upon stimulation with IgG [96,103]. Currently, there is compelling evidence of a role for mast cells in the immune response against viral infections [104]. Studies observed that viral Rev. Med. Virol. 2014; 24: 55–70. DOI: 10.1002/rmv

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62 infection of mast cells leads to the recruitment of monocytes, NK cells, and T lymphocytes [105]. The addition of dengue-specific Abs to dengue-infected mast cells leads to increased expression of RIG-I and MDA-5 and induces a profound and possibly harmful release of cytokines and chemokines. It has been concluded that FcγRIIA plays a role in the ADE of dengue infections in mast cells [106–108].

The role of Fc gamma receptors expressed on mast cells in RSV infections Mast cells express TLR4 suggesting direct recognition of pathogens including RSV. RSV infection of rodents and cows has been associated with mast cell activation. In humans, RSV bronchiolitis is associated with an increased number of mast cells [109]. Pre-treatment of mast cells with purified human total IgG results in increased amounts of chemokines compared with stimulation with RSV alone [110].

Eosinophils Although eosinophils are mostly involved in allergic reactions, they also possess antimicrobial properties [111–113]. FcγRII is responsible for Abmediating killing of tumor cells, and antibodies are able to enhance the killing ability and activate FcγRII-dependent degranulation of eosinophils against a variety of pathogens such as T. gondii and Candida albicans [111,114,115]. Abs, particularly IgG1 and IgG3 but not IgE, activate eosinophils resulting in their degranulation and causing bronchial hyperreactivity as seen in asthma patients, a process dependent on FcγRII [116]. Interestingly, immobilized IgG induces death of eosinophils, and soluble IgG is able to prolong survival of eosinophils [117]. After activation with chemoattractants or IFN-γ, FcγRI and FcγRII become membrane expressed on eosinophils. FcγRIII is mainly present intracellularly in resting eosinophils. Upon activation, however, FcγRIII becomes membrane expressed transiently before secretion of the receptor takes place [118,119]. The exact role of FcγRIII in eosinophils is yet to be determined.

The role of Fc gamma receptors expressed on eosinophils in RSV infections Increased amounts of eosinophils are observed in nasopharyngeal aspirates of RSV-infected infants compared with non-infected infants [120]. RSV replication in eosinophils results in the release of infectious virions and the pro-inflammatory Copyright © 2013 John Wiley & Sons, Ltd.

mediator interleukin 6 [121]. Eosinophils inactivate RSV by the release of a specific protein called ECP [122,123]. Infants with elevated levels of ECP during a primary RSV infection are 10 times more likely to develop wheezing later in childhood [124]. Pulmonary eosinophilia attracted in response to primary RSV infection is particularly evident in the youngest human infants and in neonatal mouse models [125,126]. Currently, no data are available concerning the effect of Abs or immune complexes on RSV-infected eosinophils. In the context of RSV vaccination, Polack et al. showed that IgG mediates increased activation of eosinophils and enhanced respiratory disease after challenge with formalininactivated RSV [38]. Therefore, abundant eosinophilic activation or ECP release might play a role in the immunopathology of RSV infections.

Basophils Basophils are a sparse subset in the population of leukocytes and they are involved in allergic reactions. Only recently, the role of FcγR on basophils is being elucidated. IgG is not able to activate basophils probably because of the high expression of the inhibitory FcγRIIB in this cell type. A low degree of basophil activation is achieved by selectively activating FcγRIIA and thereby bypassing FcγRIIB [127–130].

The role of Fc gamma receptors expressed on basophils in RSV infections RSV induces basophil accumulation in a mouse model. Furthermore, basophils were the only cells responsible for the release of interleukin 4, a cytokine that might contribute to the pulmonary pathogenesis of RSV infections [131]. No published data are available on the role of Abs and basophils in the context of RSV. Fc GAMMA RECEPTORS AND B CELLS The B cell compartment is predominantly known for its adaptive aspects in the immune defense. However, the expression of TLRs and the internalization of viruses upon binding with the BCR suggest that B cells are involved in directly sensing infectious agents [132]. A specific B cell population, called B1 cells, is already present during the fetal period. A progressive loss of B1 cells was shown with a fourfold difference between cord blood and adults above 20 years of age that indicates a specific role of B1 cells in childhood [133]. Natural Abs are spontaneously produced by B1 cells without prior Rev. Med. Virol. 2014; 24: 55–70. DOI: 10.1002/rmv

Antibodies and FcγRs in RSV infection infection or immunization and are a major recognition molecule of innate immunity [134–136]. In mice, natural Abs activate the complement system, facilitate antigen uptake, and protect against Streptococcus pneumoniae, L. monocytogenes, and influenza virus [134,137–140]. B cells only express the inhibitory FcγRIIB, and the expression of FcγRIIB varies among the different subtypes of B cells. Engagement of FcγRIIB to BCR leads to inhibition of cellular proliferation and induces apoptosis. B cells that express highaffinity BCR will receive signals from both BCR and FcγRIIB, whereas B cells that have low-affinity BCR will predominantly receive signals via FcγRIIB resulting in apoptosis. Plasma cells express high levels of FcγRIIB and are therefore susceptible to the induction of apoptosis by Abs [141]. Thus, overall, FcγRIIB acts as a regulator of humoral immunity.

The role of Fc gamma receptors expressed on B cells in RSV infections B cell responses may contribute to the protective and/or pathological effect of primary RSV infections and are increased in the acute and convalescent phase of RSV infection [142,143]. Some characteristics of RSV-specific B cells from RSV-infected individuals have been determined. B cells from RSV-infected infants younger than 3 months express fewer somatic mutations after both primary and secondary infections compared with those from individuals older than 3 months. Somatic mutation is an important property of B cells to produce neutralizing Abs upon encountering a pathogen [144]. These data suggest that inefficient somatic mutation underlies the poor Ab response in neonates against RSV infections. As mentioned before, high levels of matAbs reduce the Ab response of infants against RSV [30]. Although B cells are the main source of Abs, no study so far has investigated the effect of antibodies on the humoral response in natural RSV infections. The insufficient TLR stimulation on B cells resulting in the lack of a protective Ab response upon formalin-inactivated RSV vaccine highlights the importance of adequate activation of B cells [39]. Fc GAMMA RECEPTORS AND THE COMPLEMENT SYSTEM The complement system is a cascade that aids Abs in the clearance of pathogens. IgG1, IgG2, and IgG3 are capable of activating the classical pathway of complement. In this cascade, the formation of Copyright © 2013 John Wiley & Sons, Ltd.

63 complement factors C3a and C5a allows induction of phagocytosis and pro-inflammatory cytokines through complement receptors (C3aR and C5aR) [145]. The interplay between complement and FcγR is essential in this process (Figure 1). Pre-treatment with IgG1 is able to shift this balance by selectively activating FcγRIIB and thereby limiting the inflammatory response [146,147]

The role of Fc gamma receptors and complement in RSV infections The complement system is important in the pathogenesis of RSV infections. RSV activates the complement system and induces the production of C3a and C5a [148]. C3aR-deficient mice show decreased viral replication suggesting a nonprotective role of C3aR. The disease enhancing effect of C3aR has been confirmed in the context of the formalin-inactivated RSV vaccine. Vaccinated C5-deficient mice express an up-regulation of C3aR and enhanced respiratory disease upon infection with RSV [149]. Moreover, C3 is increased in enhanced respiratory disease caused by vaccination with formalin-inactivated RSV [38]. Both studies conclude that C3aR might contribute to the pathogenesis of RSV infection [150]. Indeed, increased complement activation has been observed in patients who died from RSV bronchiolitis [38]. The effects of pre-existent RSV-specific Abs have been studied by injecting naive mice with RSV-specific Abs to mimic infants having matAbs. The following Ab-mediated viral restriction is dependent on the complement system [60]. IgG1 is the predominant RSV-specific Ab present in infants with RSV infections and suppresses complement-mediated inflammation. This predominant interaction of IgG1 with FcγRIIB as stated by Karsten et al. is yet to be investigated in the context of RSV infections [147]. Studies on the effect of Abs on the adaptive immune response against RSV show that FcγR and complement contribute to the Ab-mediated induction of CD4+ T cells resulting in a high ratio of CD4+/CD8+ T cells [58]. The balance between CD4+ and CD8+ T cells might be important considering that patients with severe RSV infections have relatively low amounts of CD4+ T cells compared with CD8+ T cells [72,151]. A role of complement and the induction of neutralizing versus non-neutralizing Abs in shaping the CD4+/CD8+ ratio and disease severity has been suggested [58]. Rev. Med. Virol. 2014; 24: 55–70. DOI: 10.1002/rmv

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J. Jans et al.

Figure 2. Summary of the interaction between RSV, antibodies, FcγRs, and the innate immune system. In monocytic cells, the interaction between Abs and FcγRs has a neutralizing or a disease enhancing effect on RSV. FcγRIIIA+ NK cells are responsible for ADCC and induce higher amounts of cytokines in the presence of Abs, and increased amounts of FcγRIIIA+ NK cells are observed in severe RSV infections. Profound activation of neutrophils and increased cytokine release against RSV are induced in the presence of RSV-specific Abs. B cells from RSV-infected infants younger than 3 months of age express fewer somatic mutations compared with older individuals. The complement system is involved in the Ab-mediated induction of CD4+ T cells upon RSV infection

CONCLUSIONS This review has presented the extensive evidence for the immunomodulatory effect of Abs and FcγRs on innate immunity. All cells of the innate immune system express FcγRs and are affected by the presence of antibodies. Circulating matAbs should be taken into account when contemplating disease pathogenesis of infectious diseases in young infants. Most of these mechanisms are present in the context of RSV (Figure 2). Therefore, it is likely that these pathways play a significant role in the development of severe RSV infections. Currently, clinical evidence is lacking, and future research is necessary to investigate how the balance between activating and inhibitory FcγRs determines the resulting immune response during severe RSV infections. Elucidating the Ab properties, such as the neutralizing capacity, the avidity, and the titers of matAbs against RSV in young infants, could explain why matAbs are either protective or disease enhancing. In vitro experiments using primary Copyright © 2013 John Wiley & Sons, Ltd.

cells represent an important approach to studying these pathways. Characterizing the effect of Abs and activated FcγRs on neutralization of RSV in vitro, cytokine production, and the adaptive immune response could advance our knowledge on this subject. Cross-talk between Abs and innate immune receptors, such as TLRs, will be of particular interest in the context of an infection that frequently strikes young infants. Studies of FcγRdeficient mice can be used to study the effect of FcγRs in vivo. Although immune evasion mechanisms of RSV are currently being unraveled, the presence of Abs has not been investigated when contemplating clinical relevance. These mechanisms will give more insight into the effects of matAbs on the immune response and disease severity during RSV infections in infants. Second, it will provide essential knowledge relevant to the induction of protective Abs during maternal or neonatal immunization. Therefore, characterizing matAbs and the role of FcγRs will provide new Rev. Med. Virol. 2014; 24: 55–70. DOI: 10.1002/rmv

Antibodies and FcγRs in RSV infection

65

insights in the pathogenesis of RSV infections and the development of novel preventive strategies.

(N4i). G. F. and M. V. are supported by the VIRGO consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative and partially funded by the Dutch Government (BSIK 03012). O. L.’s laboratory is supported by Global Health (OPPGH5284) and Grand Challenges Explorations (OPP1035192) awards from the Bill & Melinda Gates Foundation and by National Institutes of Health grant 1R01AI100135-01.

CONFLICT OF INTEREST The authors have no competing interest. ACKNOWLEDGEMENTS J. J. is supported by a research grant of the Nijmegen Institute for Infection, Inflammation and Immunity REFERENCES 1. Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus

by interleukin 10. Annals of the Rheumatic

specific antibodies in primary respiratory

Diseases 2007; 66: 334–340.

syncytial (RS) virus infections. Journal of

infection in young children. The New

10. Banas MC, Banas B, Hudkins KL, et al.

England Journal of Medicine 2009; 360:

TLR4 links podocytes with the innate

18. Wilczynski J, Lukasik B, Torbicka E,

588–598.

immune system to mediate glomerular

Tranda I, Brzozowska-Binda A. Respira-

injury. Journal of the American Society of

tory syncytial virus (RSV) antibodies in

Nephrology 2008; 19: 704–713.

different immunoglobulin classes in small

2. Nair H, Nokes DJ, Gessner BD, et al. Global burden of acute lower respiratory infections due to respiratory syncytial

11. Rittirsch D, Flierl MA, Day DE, et al.

virus in young children: a systematic

Cross-talk between TLR4 and Fcgamma

review and meta-analysis. Lancet 2010;

ReceptorIII (CD16) pathways. PLoS Pathogens 2009; 5: e1000464.

375: 1545–1555.

Medical Virology 1985; 16: 321–328.

children. Acta Microbiologica Polonica 1994; 43: 359–368. 19. Queiroz DA, Durigon EL, Botosso VF, et al. Immune response to respiratory syncytial

3. Levy O. Innate immunity of the newborn:

12. Suara RO, Piedra PA, Glezen WP, et al.

virus in young Brazilian children. Brazilian

basic mechanisms and clinical correlates.

Prevalence of neutralizing antibody to

Journal of Medical and Biological Research

Nature Reviews Immunology 2007; 7: 379–390.

respiratory syncytial virus in sera from

4. Picard C, Casanova JL, Puel A. Infectious

mothers and newborns residing in the

20. Freitas GR, Silva DA, Yokosawa J, et al.

diseases in patients with IRAK-4, MyD88,

Gambia and in the United States. Clinical

Antibody response and avidity of respira-

NEMO,

and

tory syncytial virus-specific total IgG,

or

IkappaBalpha

deficiency.

Clinical Microbiology Reviews 2011; 24: 490–497.

Diagnostic

Laboratory

Immunology

2002; 35: 1183–1193.

IgG1, and IgG3 in young children. Journal

1996; 3: 477–479. 13. Hacimustafaoglu M, Celebi S, Aynaci E,

of Medical Virology 2011; 83: 1826–1833.

5. He W, Ladinsky MS, Huey-Tubman KE,

et al. The progression of maternal RSV

21. Parrott RH, Kim HW, Arrobio JO, et al.

Jensen GJ, McIntosh JR, Bjorkman PJ.

antibodies in the offspring. Archives of

Epidemiology of respiratory syncytial

FcRn-mediated antibody transport across

Disease in Childhood 2004; 89: 52–53.

virus infection in Washington, D.C. II.

epithelial cells revealed by electron tomography. Nature 2008; 455: 542–546. 6. Weaver LT, Arthur HM, Bunn JE, Thomas JE.

14. Nokes DJ, Okiro EA, Ngama M, et al.

immunologic

ogy

American Journal of Epidemiology 1973; 98:

in

a

birth

cohort

from

Kilifi

Human milk IgA concentrations during the

district, Kenya: infection during the first

first year of lactation. Archives of Disease in

year of life. The Journal of Infectious

Childhood 1998; 78: 235–239.

Infection and disease with respect to age,

Respiratory syncytial virus epidemiol-

Diseases 2004; 190: 1828–1832.

status,

race

and

sex.

289–300. 22. Bulkow LR, Singleton RJ, Karron RA, Harrison LH, Alaska RSVSG. Risk factors

7. Winkelstein JA, Marino MC, Lederman HM,

15. Brandenburg AH, Groen J, van Steensel-

for severe respiratory syncytial virus infec-

et al. X-linked agammaglobulinemia: re-

Moll HA, et al. Respiratory syncytial virus

tion among Alaska native children. Pediat-

port on a United States registry of 201

specific serum antibodies in infants under

patients. Medicine (Baltimore) 2006; 85:

six months of age: limited serological re-

23. Stensballe LG, Ravn H, Kristensen K, et al.

193–202.

sponse upon infection. Journal of Medical

Respiratory syncytial virus neutralizing

Virology 1997; 52: 97–104.

antibodies in cord blood, respiratory syn-

8. Ravetch JV, Bolland S. IgG Fc receptors. An-

rics 2002; 109: 210–216.

nual Review of Immunology 2001; 19: 275–290.

16. Welliver RC, Kaul TN, Putnam TI, Sun M,

cytial virus hospitalization, and recurrent

9. van Lent PL, Blom AB, Grevers L,

Riddlesberger K, Ogra PL. The antibody

wheeze. The Journal of Allergy and Clinical Immunology 2009; 123: 398–403.

Sloetjes A, van den Berg WB. Toll-like

response

receptor 4 induced FcgammaR expression

infection with respiratory syncytial virus:

24. Glezen WP, Paredes A, Allison JE,

to

primary

and

secondary

potentiates early onset of joint inflamma-

kinetics of class-specific responses. The

Taber LH, Frank AL. Risk of respiratory

tion and cartilage destruction during im-

Journal of Pediatrics 1980; 96: 808–813.

syncytial virus infection for infants from

mune complex arthritis: Toll-like receptor

17. Hornsleth A, Bech-Thomsen N, Friis B.

low-income families in relationship to

4 largely regulates FcgammaR expression

Detection by ELISA of IgG-subclass-

age, sex, ethnic group, and maternal

Copyright © 2013 John Wiley & Sons, Ltd.

Rev. Med. Virol. 2014; 24: 55–70. DOI: 10.1002/rmv

J. Jans et al.

66 antibody level. The Journal of Pediatrics

antibodies. Clinics (São Paulo, Brazil) 2007;

1981; 98: 708–715.

62: 709–716.

The Journal of Infectious Diseases 2010; 201: 923–935.

25. Ogilvie MM, Vathenen AS, Radford M,

34. Committee on Infectious D. From the

44. Modhiran N, Kalayanarooj S, Ubol S.

Codd J, Key S. Maternal antibody and

American Academy of Pediatrics: policy

Subversion of innate defenses by the

respiratory syncytial virus infection in in-

statements—modified

recommendations

interplay between DENV and pre-existing

fancy. Journal of Medical Virology 1981; 7:

for use of palivizumab for prevention of

enhancing antibodies: TLRs signaling

263–271.

respiratory

infections.

collapse. PLoS Neglected Tropical Diseases

Taber LH, Glezen WP. Relation of serum

35. Blanken MO, Rovers MM, Molenaar JM,

45. Boonnak K, Slike BM, Burgess TH, et al.

antibody to glycoproteins of respiratory

et al. Respiratory syncytial virus and

Role of dendritic cells in antibody-

syncytial virus with immunity to infection

recurrent wheeze in healthy preterm in-

dependent enhancement of dengue virus

in children. Viral Immunology 1987; 1:

fants. The New England Journal of Medicine

infection. Journal of Virology 2008; 82:

199–205.

2013; 368: 1791–1799.

26. Kasel JA, Walsh EE, Frank AL, Baxter BD,

syncytial

virus

Pediatrics 2009; 124: 1694–1701.

2010; 4: e924.

3939–3951.

27. Eick A, Karron R, Shaw J, et al. The role

36. Boyoglu-Barnum S, Gaston KA, Todd SO,

of neutralizing antibodies in protection

et al. A respiratory syncytial virus (RSV)

Salmon JE. Human immunodeficiency

of American Indian infants against respi-

anti-G protein F(ab’)2 monoclonal anti-

virus infection of monocytes: relationship

ratory syncytial virus disease. The Pediatric

body suppresses mucous production and

to Fc-gamma receptors and antibody-

Infectious Disease Journal 2008; 27: 207–212.

breathing effort in RSV rA2-line19F-

dependent viral enhancement. Immunology

28. Nielsen HE, Siersma V, Andersen S, et al. Respiratory syncytial virus infection—

infected Balb/c mice. Journal of Virology

46. Laurence

J,

Saunders

A,

Early

E,

1990; 70: 338–343. 47. Takeda A, Sweet RW, Ennis FA. Two recep-

2013; 87(20): 10955–10967.

risk factors for hospital admission: a

37. Caidi H, Harcourt JL, Tripp RA, Anderson LJ,

tors are required for antibody-dependent

case–control study. Acta Paediatrica 2003; 92:

Haynes LM. Combination therapy using

enhancement of human immunodeficiency

1314–1321.

monoclonal antibodies against respiratory

virus type 1 infection: CD4 and Fc gamma

29. Murphy BR, Alling DW, Snyder MH, et al.

syncytial virus (RSV) G glycoprotein protects

R. Journal of Virology 1990; 64: 5605–5610.

Effect of age and preexisting antibody on

from RSV disease in BALB/c mice. PLoS One

48. Chareonsirisuthigul T, Kalayanarooj S,

serum antibody response of infants and

Ubol S. Dengue virus (DENV) antibody-

2012; 7: e51485.

children to the F and G glycoproteins dur-

38. Polack FP, Teng MN, Collins PL, et al. A

ing respiratory syncytial virus infection.

role for immune complexes in enhanced

upregulates

Journal of Clinical Microbiology 1986; 24:

respiratory syncytial virus disease. The

inflammatory cytokines, but suppresses

Journal of Experimental Medicine 2002; 196:

anti-DENV

859–865.

inflammatory cytokine production, in

894–898. 30. Shinoff JJ, O’Brien KL, Thumar B, et al.

dependent

enhancement the free

of

infection

production radical

of and

antipro-

THP-1 cells. The Journal of General Virology

Young infants can develop protective

39. Delgado MF, Coviello S, Monsalvo AC,

levels of neutralizing antibody after infec-

et al. Lack of antibody affinity maturation

tion with respiratory syncytial virus. The

due to poor Toll-like receptor stimulation

49. Halstead SB, Mahalingam S, Marovich MA,

Journal of Infectious Diseases 2008; 198:

leads to enhanced respiratory syncytial

Ubol S, Mosser DM. Intrinsic antibody-

1007–1015.

virus disease. Nature Medicine 2009; 15:

dependent enhancement of microbial infec-

34–41.

tion in macrophages: disease regulation by

31. Murphy BR, Collins PL, Lawrence L, Zubak J, Chanock RM, Prince GA. Immu-

40. Moghaddam A, Olszewska W, Wang B,

nosuppression of the antibody response

et al. A potential molecular mechanism

to respiratory syncytial virus (RSV) by

for hypersensitivity caused by formalin-

pre-existing

inactivated

serum

antibodies:

partial

prevention by topical infection of the respiratory tract with vaccinia virus-RSV recombinants.

The

Journal

of

General

vaccines.

Nature

Medicine

2006; 12: 905–907.

32. Crowe JE, Jr. Influence of maternal

immune complexes. The Lancet Infectious Diseases 2010; 10: 712–722. 50. Tridandapani S, Siefker K, Teillaud JL, Carter JE, Wewers MD, Anderson CL. Regulated

expression

and

inhibitory

41. Castilow EM, Olson MR, Varga SM.

function of Fcgamma RIIb in human

Understanding respiratory syncytial virus

monocytic cells. The Journal of Biological

(RSV) vaccine-enhanced disease. Immuno-

Virology 1989; 70(Pt 8): 2185–2190.

2007; 88: 365–375.

logic Research 2007; 39: 225–239.

Chemistry 2002; 277: 5082–5089. 51. Zhang Y, Liu S, Liu J, et al. Immune complex/Ig negatively regulate TLR4-

antibodies on neonatal immunization

42. Underhill DM, Ozinsky A. Phagocytosis

Clinical

of microbes: complexity in action. Annual

triggered

Review of Immunology 2002; 20: 825–852.

macrophages through Fc gamma RIIb-

against

respiratory

viruses.

Infectious Diseases 2001; 33: 1720–1727. 33. Vieira SE, Gilio AE, Durigon EL, Ejzenberg B.

43. Ubol S, Phuklia W, Kalayanarooj S,

inflammatory

response

in

dependent PGE2 production. Journal of Immunology 2009; 182: 554–562.

infection

Modhiran N. Mechanisms of immune

caused by respiratory syncytial virus in

evasion induced by a complex of dengue

52. Dhodapkar KM, Kaufman JL, Ehlers M,

infants: the role played by specific

virus and preexisting enhancing antibodies.

et al. Selective blockade of inhibitory

Lower

respiratory

tract

Copyright © 2013 John Wiley & Sons, Ltd.

Rev. Med. Virol. 2014; 24: 55–70. DOI: 10.1002/rmv

Antibodies and FcγRs in RSV infection

67 72. Ahmad R, Sindhu ST, Toma E, et al.

human

61. Fuentes S, Tran KC, Luthra P, Teng MN,

dendritic cell maturation with IL-12p70

He B. Function of the respiratory syncytial

Evidence

production and immunity to antibody-

virus small hydrophobic protein. Journal of

antibody-dependent cellular cytotoxicity-

Virology 2007; 81: 8361–8366.

mediating

Fcgamma

receptor

enables

coated tumor cells. Proceedings of the National Academy of Sciences of the United

for

a

correlation

anti-HIV-1

between

antibodies

and

62. Spann KM, Tran KC, Chi B, Rabin RL,

prognostic predictors of HIV infection. Journal of Clinical Immunology 2001; 21:

States of America 2005; 102: 2910–2915.

Collins PL. Suppression of the induction

53. Dhodapkar KM, Banerjee D, Connolly J,

of alpha, beta, and lambda interferons by

et al. Selective blockade of the inhibitory

the NS1 and NS2 proteins of human respi-

73. Kohl S. Defective infant antiviral cytotox-

Fcgamma receptor (FcgammaRIIB) in

ratory syncytial virus in human epithelial

icity to herpes simplex virus-infected cells.

human dendritic cells and monocytes

cells and macrophages [corrected]. Journal

induces a type I interferon response

of Virology 2004; 78: 4363–4369.

program. The Journal of Experimental

227–233.

The Journal of Pediatrics 1983; 102: 885–888. 74. Jenkins M, Mills J, Kohl S. Natural

63. Senft AP, Taylor RH, Lei W, et al.

killer cytotoxicity and antibody-dependent

Respiratory syncytial virus impairs macro-

cellular cytotoxicity of human immunodefi-

54. Gimenez HB, Chisholm S, Dornan J,

phage IFN-alpha/beta- and IFN-gamma-

ciency virus-infected cells by leukocytes

Cash P. Neutralizing and enhancing

stimulated transcription by distinct mech-

from human neonates and adults. Pediatric

activities of human respiratory syncytial

anisms. American Journal of Respiratory Cell

virus-specific antibodies. Clinical and Di-

and Molecular Biology 2010; 42: 404–414.

agnostic Laboratory Immunology 1996; 3:

64. Jie Z, Dinwiddie DL, Senft AP, Harrod KS.

Sanchez-Pescador L, Kohl S. Human fetal

Regulation of STAT signaling in mouse

antibody-dependent cellular cytotoxicity to

55. Gimenez HB, Keir HM, Cash P. In vitro

bone marrow derived dendritic cells by

herpes simplex virus-infected cells. Pediatric

enhancement of respiratory syncytial virus

respiratory syncytial virus. Virus Research

infection of U937 cells by human sera. The

2011; 156: 127–133.

Medicine 2007; 204: 1359–1369.

280–286.

Journal of General Virology 1989; 70(Pt 1): 89–96.

in

Research 1994; 35: 289–292. 76. Ernst LK, Metes D, Herberman RB, Morel PA.

65. Tregoning JS, Schwarze J. Respiratory viral infections

Research 1993; 33: 469–474. 75. Landers DV, Smith JP, Walker CK, Milam T,

infants:

causes,

Allelic

polymorphisms

in

the

clinical

FcgammaRIIC gene can influence its

Anderson

R.

symptoms,

immunology.

function on normal human natural

enhancement

of

Clinical Microbiology Reviews 2010; 23: 74–98.

killer cells. Journal of Molecular Medicine

respiratory syncytial virus infection by sera

66. Perussia B. Fc receptors on natural killer

from young infants. Clinical and Diagnostic

cells. Current Topics in Microbiology and

56. Osiowy

C,

Horne

Antibody-dependent

D,

Laboratory Immunology 1994; 1: 670–677.

virology,

and

Immunology 1998; 230: 63–88.

(Berlin) 2002; 80: 248–257. 77. Morel PA, Ernst LK, Metes D. Functional CD32 molecules on human NK cells. Leukemia and Lymphoma 1999; 35: 47–56.

57. Gonzalez PA, Bueno SM, Carreno LJ,

67. Fauriat C, Long EO, Ljunggren HG,

Riedel CA, Kalergis AM. Respiratory syncy-

Bryceson YT. Regulation of human NK-

78. Dutertre CA, Bonnin-Gelize E, Pulford K,

tial virus infection and immunity. Reviews in

cell cytokine and chemokine production

Bourel D, Fridman WH, Teillaud JL. A

Medical Virology 2012; 22: 230–244.

by target cell recognition. Blood 2010; 115:

novel subset of NK cells expressing high

2167–2176.

levels of inhibitory FcgammaRIIB modu-

58. Kruijsen D, Bakkers MJ, van Uden NO,

lating antibody-dependent function. Journal

et al. Serum antibodies critically affect

68. Sulica A, Morel P, Metes D, Herberman RB.

virus-specific CD4+/CD8+ T cell balance

Ig-binding receptors on human NK cells as

of Leukocyte Biology 2008; 84: 1511–1520.

during respiratory syncytial virus infec-

effector and regulatory surface molecules.

79. Hussell T, Openshaw PJ. Intracellular IFN-

tions. The Journal of Immunology 2010; 185:

International Reviews of Immunology 2001;

gamma expression in natural killer cells

6489–6498.

20: 371–414.

precedes lung CD8+ T cell recruitment

59. Bukreyev A, Yang L, Fricke J, et al. The

Close

during respiratory syncytial virus infec-

secreted form of respiratory syncytial

encounters of different kinds: dendritic

tion. The Journal of General Virology 1998;

virus G glycoprotein helps the virus evade

cells and NK cells take centre stage. Nature

antibody-mediated restriction of replica-

Reviews Immunology 2005; 5: 112–124.

tion by acting as an antigen decoy and

70. Sulica A, Galatiuc C, Manciulea M, et al.

killer cells are involved in acute lung

through effects on Fc receptor-bearing

Regulation of human natural cytotoxicity

immune injury caused by respiratory

leukocytes. Journal of Virology 2008; 82:

by IgG. IV. Association between binding

syncytial virus infection. Journal of Virology

12191–12204.

of monomeric IgG to the Fc receptors on

69. Degli-Esposti

MA, Smyth

MJ.

79(Pt 11): 2593–2601. 80. Li F, Zhu H, Sun R, Wei H, Tian Z. Natural

2012; 86: 2251–2258.

60. Bukreyev A, Yang L, Collins PL. The

large granular lymphocytes and inhibition

81. Scott R, de Landazuri MO, Gardner PS,

secreted G protein of human respiratory

of natural killer (NK) cell activity. Cellular

Owen JJ. Human antibody-dependent

syncytial virus antagonizes antibody-

Immunology 1993; 147: 397–410.

cell-mediated cytotoxicity against target

mediated restriction of replication involv-

71. Ahmad A, Menezes J. Antibody-dependent

cells infected with respiratory syncytial

ing macrophages and complement. Journal

cellular cytotoxicity in HIV infections.

virus. Clinical and Experimental Immunology

of Virology 2012; 86: 10880–10884.

FASEB Journal 1996; 10: 258–266.

1977; 28: 19–26.

Copyright © 2013 John Wiley & Sons, Ltd.

Rev. Med. Virol. 2014; 24: 55–70. DOI: 10.1002/rmv

J. Jans et al.

68 82. Okabe N, Hashimoto G, Abo T, Wright PF,

91. Smith KG, Clatworthy MR. FcgammaRIIB

101. Okayama Y, Hagaman DD, Woolhiser M,

Karzon DT. Characterization of the human

in autoimmunity and infection: evolution-

Metcalfe DD. Further characterization of

peripheral blood effector cells mediating

ary and therapeutic implications. Nature

FcgammaRII and FcgammaRIII expression

antibody-dependent cell-mediated cyto-

Reviews Immunology 2010; 10: 328–343.

by cultured human mast cells. International

toxicity against respiratory syncytial virus.

92. Lukens MV, van de Pol AC, Coenjaerts FE,

Archives of Allergy and Immunology 2001;

Clinical Immunology and Immunopathology

et al. A systemic neutrophil response

1983; 27: 200–209.

precedes robust CD8(+) T-cell activation

102. Malbec O, Attal JP, Fridman WH, Daeron M.

83. Welliver TP, Garofalo RP, Hosakote Y,

during natural respiratory syncytial virus

Negative regulation of mast cell proliferation

et al. Severe human lower respiratory

infection in infants. Journal of Virology

by FcgammaRIIB. Molecular Immunology

tract illness caused by respiratory syncy-

2010; 84: 2374–2383.

124: 155–157.

2002; 38: 1295–1299.

tial virus and influenza virus is character-

93. Kaul TN, Faden H, Ogra PL. Effect of

103. Takai T, Ono M, Hikida M, Ohmori H,

ized by the absence of pulmonary

respiratory syncytial virus and virus-

Ravetch JV. Augmented humoral and ana-

The

antibody complexes on the oxidative me-

phylactic responses in Fc gamma RII-

Journal of Infectious Diseases 2007; 195:

tabolism of human neutrophils. Infection

1126–1136.

and Immunity 1981; 32: 649–654.

cytotoxic

lymphocyte

responses.

deficient mice. Nature 1996; 379: 346–349. 104. Marshall JS. Mast-cell responses to patho-

84. Tripp RA, Moore D, Barskey A, et al.

94. Faden H, Kaul TN, Ogra PL. Activation of

Peripheral blood mononuclear cells from

oxidative and arachidonic acid metabo-

infants hospitalized because of respiratory

lism in neutrophils by respiratory syncy-

105. Burke SM, Issekutz TB, Mohan K, Lee PW,

syncytial virus infection express T helper-1

tial virus antibody complexes: possible

Shmulevitz M, Marshall JS. Human mast

and T helper-2 cytokines and CC chemo-

role in disease. The Journal of Infectious

cell activation with virus-associated stim-

kine messenger RNA. The Journal of

Diseases 1983; 148: 110–116.

uli leads to the selective chemotaxis of nat-

Infectious Diseases 2002; 185: 1388–1394.

95. Arnold

R,

Werner

F,

Humbert

B,

gens. Nature Reviews Immunology 2004; 4: 787–799.

ural killer cells by a CXCL8-dependent mechanism. Blood 2008; 111: 5467–5476.

85. Perussia B, Dayton ET, Lazarus R, Fanning

Werchau H, Konig W. Effect of respiratory

V, Trinchieri G. Immune interferon induces

syncytial virus-antibody complexes on

106. King CA, Anderson R, Marshall JS. Den-

the receptor for monomeric IgG1 on

cytokine (IL-8, IL-6, TNF-alpha) release and

gue virus selectively induces human mast

human monocytic and myeloid cells. The

respiratory burst in human granulocytes.

cell chemokine production. Journal of Virol-

Journal of Experimental Medicine 1983; 158:

Immunology 1994; 82: 184–191.

1092–1113.

ogy 2002; 76: 8408–8419.

96. Malbec O, Daeron M. The mast cell IgG

107. Brown MG, King CA, Sherren C, Marshall JS,

86. Selvaraj P, Fifadara N, Nagarajan S,

receptors and their roles in tissue inflam-

Anderson

Cimino A, Wang G. Functional regulation

mation. Immunological Reviews 2007; 217:

FcgammaRII

206–221.

dengue virus infection of human mast

of human neutrophil Fc gamma receptors. Immunologic Research 2004; 29: 219–230.

97. Okayama Y, Kirshenbaum AS, Metcalfe DD.

R.

A

dominant

in

role

for

antibody-enhanced

cells and associated CCL5 release. Journal of Leukocyte Biology 2006; 80: 1242–1250.

87. Nagarajan S, Fifadara NH, Selvaraj P.

Expression of a functional high-affinity

Signal-specific activation and regulation

IgG receptor, Fc gamma RI, on human

of human neutrophil Fc gamma recep-

mast

IFN-

et al. RNA sensors enable human mast cell

tors. Journal of Immunology 2005; 174:

gamma. Journal of Immunology 2000;

anti-viral chemokine production and IFN-

5423–5432.

164: 4332–4339.

mediated

cells:

up-regulation

by

108. Brown MG, McAlpine SM, Huang YY,

protection

in

response

to

88. Huizinga TW, Roos D, von dem Borne AE.

98. Woolhiser MR, Okayama Y, Gilfillan AM,

Neutrophil Fc-gamma receptors: a two-

Metcalfe DD. IgG-dependent activation

way bridge in the immune system. Blood

of human mast cells following up-

109. Everard ML, Fox G, Walls AF, et al.

1990; 75: 1211–1214.

regulation of FcgammaRI by IFN-gamma.

Tryptase and IgE concentrations in the re-

European Journal of Immunology 2001; 31:

spiratory tract of infants with acute bron-

3298–3307.

chiolitis. Archives of Disease in Childhood

89. Coxon A, Cullere X, Knight S, et al. Fc gamma RIII mediates neutrophil recruit-

antibody-enhanced dengue virus infection. PLoS One 2012; 7: e34055.

ment to immune complexes. A mechanism

99. Woolhiser MR, Brockow K, Metcalfe DD.

for neutrophil accumulation in immune-

Activation of human mast cells by

110. Al-Afif A. Human mast cell responses to

mediated inflammation. Immunity 2001;

aggregated IgG through FcgammaRI: ad-

respiratory syncytial virus. In Volume ed.

14: 693–704.

ditive effects of C3a. Clinical Immunology

90. Marois L, Pare G, Vaillancourt M, Rollet-Labelle

Naccache

Fc

100. Hazenbos WL, Gessner JE, Hofhuis FM,

Fc gamma R-mediated killing by eosino-

et al. Impaired IgG-dependent anaphylaxis

phils. Journal of Immunology 1989; 142:

calcium influx in IgG-mediated responses

and Arthus reaction in Fc gamma RIII

in human neutrophils. The Journal of Biologi-

(CD16) deficient mice. Immunity 1996; 5:

cal Chemistry 2011; 286: 3509–3519.

181–188.

triggers

PH.

Halifax, Novia Scotia, 2011. 111. Graziano RF, Looney RJ, Shen L, Fanger MW.

raft-dependent

gammaRIIIb

E,

2004; 110: 172–180.

1995; 72: 64–69.

Copyright © 2013 John Wiley & Sons, Ltd.

230–235. 112. Adamko DJ, Yost BL, Gleich GJ, Fryer AD, Jacoby DB. Ovalbumin sensitization

Rev. Med. Virol. 2014; 24: 55–70. DOI: 10.1002/rmv

Antibodies and FcγRs in RSV infection

69

changes the inflammatory response to sub-

their role in host defense against respiratory

134. Carroll MC. The role of complement and

sequent parainfluenza infection. Eosinophils

virus pathogens. Journal of Leukocyte Biology

complement receptors in induction and

mediate airway hyperresponsiveness, m(2)

2001; 70: 691–698.

regulation of immunity. Annual Review of Immunology 1998; 16: 545–568.

and

124. Pifferi M, Ragazzo V, Caramella D, Baldini G.

antiviral effects. The Journal of Experimental

Eosinophil cationic protein in infants with

135. Dorshkind K, Montecino-Rodriguez E.

Medicine 1999; 190: 1465–1478.

muscarinic

receptor

dysfunction,

respiratory syncytial virus bronchiolitis:

Fetal B-cell lymphopoiesis and the emer-

113. Rosenberg HF, Dyer KD, Domachowske JB.

predictive value for subsequent development

gence of B-1-cell potential. Nature Reviews

Eosinophils and their interactions with

of persistent wheezing. Pediatric Pulmonology

respiratory virus pathogens. Immunologic

2001; 31: 419–424.

Research 2009; 43: 128–137.

Immunology 2007; 7: 213–219. 136. Capolunghi F, Cascioli S, Giorda E, et al.

125. Johnson TR, Graham BS. Contribution of

CpG drives human transitional B cells to

respiratory syncytial virus G antigenicity

terminal differentiation and production of

Functions of the various IgG Fc receptors

to

natural antibodies. Journal of Immunology

in mediating killing of Toxoplasma gondii.

implications for severe disease during

Journal of Immunology 1991; 146: 3145–3151.

primary respiratory syncytial virus infec-

137. Avrameas S. Natural autoantibodies: from

115. Ikeda Y, Mita H, Kudo M, Hasegawa M,

tion. The Pediatric Infectious Disease Journal

‘horror autotoxicus’ to ‘gnothi seauton’.

114. Erbe DV, Pfefferkorn ER, Fanger MW.

Akiyama K. Degranulation of eosinophils by IgG antibody to Candida antigen. Arerugī 1999; 48: 546–553. 116. Kaneko M, Swanson MC, Gleich GJ, Kita H. Allergen-specific IgG1 and IgG3 through

vaccine-enhanced

illness

and

the

2004; 23: S46-S57.

2008; 180: 800–808.

Immunology Today 1991; 12: 154–159.

126. Rosenberg HF, Dyer KD, Domachowske

138. Thornton BP, Vetvicka V, Ross GD. Natu-

JB. Respiratory viruses and eosinophils:

ral antibody and complement-mediated

exploring the connections. Antiviral Re-

antigen processing and presentation by B

search 2009; 83: 1–9.

lymphocytes. Journal of Immunology 1994; 152: 1727–1737.

Fc gamma RII induce eosinophil degranu-

127. Anselmino LM, Perussia B, Thomas LL.

lation. The Journal of Clinical Investigation

Human basophils selectively express the

139. Ochsenbein AF, Fehr T, Lutz C, et al. Con-

1995; 95: 2813–2821.

Fc gamma RII (CDw32) subtype of IgG

trol of early viral and bacterial distribution

receptor. The Journal of Allergy and Clinical

and disease by natural antibodies. Science

117. Kim JT, Schimming AW, Kita H. Ligation of Fc gamma RII (CD32) pivotally regulates survival of human eosinophils. Journal of Immunology 1999; 162: 4253–4259. 118. Hartnell A, Kay AB, Wardlaw AJ. IFNgamma induces expression of Fc gamma RIII (CD16) on human eosinophils. Journal

Immunology 1989; 84: 907–914.

1999; 286: 2156–2159.

128. Takahashi K, Takada M. Detection of

140. Baumgarth N, Herman OC, Jager GC,

IgG receptor subtype on basophils using

Brown LE, Herzenberg LA, Chen J. B-1

two-color FCM. Nihon Rinsho 1992; 50:

and B-2 cell-derived immunoglobulin M

2455–2459.

antibodies are nonredundant components

129. Cady CT, Powell MS, Harbeck RJ, et al. IgG

of the protective response to influenza

antibodies produced during subcutaneous

virus infection. The Journal of Experimental

119. Zhu X, Hamann KJ, Munoz NM, et al. Intra-

allergen immunotherapy mediate inhibition

Medicine 2000; 192: 271–280.

cellular expression of Fc gamma RIII (CD16)

of basophil activation via a mechanism involv-

141. Nimmerjahn F, Ravetch JV. Fc-receptors as

and its mobilization by chemoattractants in

ing both FcgammaRIIA and FcgammaRIIB.

regulators of immunity. Advances in Immu-

human eosinophils. Journal of Immunology

Immunology Letters 2010; 130: 57–65.

of Immunology 1992; 148: 1471–1478.

nology 2007; 96: 179–204.

130. Cassard L, Jonsson F, Arnaud S, Daeron

142. Raes M, Peeters V, Alliet P, et al. Peripheral

120. Okamoto N, Ikeda M, Okuda M, et al.

M. Fcgamma receptors inhibit mouse and

blood T and B lymphocyte subpopulations

Increased eosinophilic cationic protein in

human basophil activation. Journal of

in infants with acute respiratory syncytial

nasal fluid in hospitalized wheezy infants

Immunology 2012; 189: 2995–3006.

virus brochiolitis. Pediatric Allergy and Im-

1998; 161: 2574–2579.

with RSV infection. Allergology Interna-

131. Moore ML, Newcomb DC, Parekh VV,

munology 1997; 8: 97–102.

et al. STAT1 negatively regulates lung

143. Reed JL, Welliver TP, Sims GP, et al. Innate

121. Dyer KD, Percopo CM, Fischer ER,

basophil IL-4 expression induced by respi-

immune signals modulate antiviral and

Gabryszewski SJ, Rosenberg HF. Pneumo-

ratory syncytial virus infection. Journal of

polyreactive antibody responses during

viruses infect eosinophils and elicit MyD88-

Immunology 2009; 183: 2016–2026.

severe respiratory syncytial virus infec-

tional 2011; 60: 467–472.

dependent

release

of

chemoattractant

132. Browne EP. Regulation of B-cell responses

cytokines and interleukin-6. Blood 2009;

by Toll-like receptors. Immunology 2012;

114: 2649–2656.

136: 370–379.

tion. The Journal of Infectious Diseases 2009; 199: 1128–1138. 144. Williams JV, Weitkamp JH, Blum DL,

122. Soukup JM, Becker S. Role of monocytes

133. Griffin DO, Holodick NE, Rothstein TL.

LaFleur BJ, Crowe JE, Jr. The human

and eosinophils in human respiratory

Human B1 cells in umbilical cord and

neonatal B cell response to respiratory

syncytial virus infection in vitro. Clinical

adult peripheral blood express the novel

syncytial virus uses a biased antibody

Immunology 2003; 107: 178–185.

phenotype CD20+ CD27+ CD43+ CD70.

variable

The Journal of Experimental Medicine 2011;

somatic mutations. Molecular Immunology

208: 67–80.

2009; 47: 407–414.

123. Rosenberg

HF,

Domachowske

JB.

Eosinophils, eosinophil ribonucleases, and

Copyright © 2013 John Wiley & Sons, Ltd.

gene

repertoire

that

lacks

Rev. Med. Virol. 2014; 24: 55–70. DOI: 10.1002/rmv

J. Jans et al.

70 M,

150. Bera MM, Lu B, Martin TR, et al. Th17

Reis ES, Kohl J. The role of the anaphy-

Henson PM. Activation of complement

cytokines are critical for respiratory syncy-

latoxins in health and disease. Molecular

by cells infected with respiratory syncytial

tial virus-associated airway hyperreponsive

Immunology 2009; 46: 2753–2766.

virus. Infection and Immunity 1981; 33:

ness through regulation by complement

43–48.

C3a and tachykinins. Journal of Immunology

145. Klos A, Tenner AJ, Johswich KO, Ager RR,

146. Ricklin D, Reis ES, Lambris JD. A sweet spot to control complement-induced inflamma-

148. Smith

TF,

McIntosh

K,

Fishaut

149. Melendi GA, Hoffman SJ, Karron RA,

2011; 187: 4245–4255.

hyper-

151. Brand HK, Ferwerda G, Preijers F, et al.

147. Karsten CM, Pandey MK, Figge J, et al.

reactivity and pulmonary eosinophilia

CD4+ T-cell counts and interleukin-8 and

Anti-inflammatory activity of IgG1 medi-

during enhanced respiratory syncytial

CCL-5 plasma concentrations discriminate

ated by Fc galactosylation and association

virus disease by decreasing C3a receptor

disease severity in children with RSV

of FcgammaRIIB and dectin-1. Nature

expression. Journal of Virology 2007; 81:

infection. Pediatric Research 2013; 73:

Medicine 2012; 18: 1401–1406.

991–999.

187–193.

tion. Nature Medicine 2012; 18: 1340–1341.

et

Copyright © 2013 John Wiley & Sons, Ltd.

al.

C5

modulates

airway

Rev. Med. Virol. 2014; 24: 55–70. DOI: 10.1002/rmv